Stimulant-induced excitatory and inhibitory dopamine receptor signaling and trafficking

兴奋剂诱导的兴奋性和抑制性多巴胺受体信号传导和运输

• 批准号: 10734322
• 负责人: Christin Y. Sander
• 金额: $ 69.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734322
• 关键词: Acute; Address; Affect; Amphetamines; Animal Model; Behavior; Brain; Chronic; Complex; Data; Development; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dopamine Uptake Inhibitors; Drug Addiction; Drug Exposure; Drug Kinetics; Drug Sensitization; Drug abuse; Drug usage; Drug user; Equilibrium; Evolution; Experimental Designs; Exposure to; Functional Magnetic Resonance Imaging; Goals; Hour; Image; In Vitro; Injections; Knowledge; Lead; Maintenance; Measures; Membrane; Methodology; Methods; Molecular; Multimodal Imaging; Neurobiology; Neuropharmacology; Outcome; Pathogenesis; Pharmaceutical Preparations; Play; Positron-Emission Tomography; Prevention; Raclopride; Receptor Signaling; Recovery; Recycling; Reporting; Ritalin; Role; Sensory Receptors; Signal Transduction; Stimulant; Substance Use Disorder; Synapses; Testing; Time; addiction; antagonist; dopamine system; dopamine transporter; extracellular; imaging study; in vivo; innovation; insight; neurobiological mechanism; neuroimaging; nonhuman primate; pharmacologic; prevent; psychostimulant; radiotracer; receptor; receptor internalization; receptor recycling; response; stimulant abuse; stimulant exposure; stimulant use; timeline; trafficking; translation to humans; uptake

Project Summary The dopamine system plays a major role in the pathogenesis of substance use disorders. Stimulant drug use and abuse lead to several dopaminergic alterations that contribute to the complex behavior associated with the formation of addiction. A single acute exposure to a stimulant drug can trigger receptor internalization as an early synaptic adaptation mechanism to high dopamine concentrations. These mechanisms have been shown to affect neuroimaging outcomes, specifically positron emission tomography (PET), which has revealed paradoxically long reductions in dopamine D2/D3 receptor availability after stimulant-induced dopamine release. To date, we still have a limited understanding of the timeline of dopamine receptor internalization and recovery with repeated drug exposure and how these adaptation mechanisms affect whole-brain signaling of both excitatory D1 and inhibitory D2-type receptors. This study aims to address this knowledge gap by characterizing how two classes of stimulant drugs (amphetamine and methylphenidate) modulate dopamine receptor subtype signaling and receptor trafficking over time. Using state-of-the-art simultaneous PET and functional magnetic resonance imaging (fMRI) methodology in non-human primates, the timescales of amphetamine-induced receptor internalization and recycling will be established using repeated amphetamine administrations. Targeted dopaminergic blocking drugs will be paired with amphetamine to determine how the balance between excitatory D1 and inhibitory D2 receptor signaling and trafficking is modulated over time. The effects of repeated amphetamine will then be compared to those of methylphenidate to assess varying levels of dopamine surges and differential mechanisms of action across these two stimulant drugs. Overall, this study will unravel brain- wide molecular and functional changes due to repeated stimulant drug exposure by imaging the timescales of dopamine receptor trafficking in the living brain in a translational animal model. The results will elucidate the role of dopamine D1 and D2-type receptor adaptations, thereby providing important insight into the neurobiological mechanisms involved in repeated stimulant drug use relevant for initiating and eventually preventing drug sensitization and addiction.

项目摘要 多巴胺系统在物质使用障碍的发病机理中起着重要作用。使用刺激性药物 滥用导致几种多巴胺能改变，这有助于与之相关的复杂行为 成瘾的形成。单一急性暴露于刺激性药物可以触发受体内在化，作为早期 突触适应机制对高多巴胺浓度。这些机制已显示出影响 神经影像学的结果，特别是正面发射断层扫描（PET），它矛盾地揭示了 刺激性诱导的多巴胺释放后多巴胺D2/D3受体的可用性的长长降低。迄今为止，我们 对多巴胺受体内在化和恢复的时间表仍然有限 药物暴露以及这些适应机制如何影响兴奋性D1和 抑制性D2型受体。这项研究旨在通过表征两个课程来解决这一知识差距 刺激性药物（苯丙胺和哌醋甲酯）调节多巴胺受体亚型信号和 随着时间的流逝，受体贩运。使用最新的同时宠物和功能性磁共振 非人类灵长类动物的成像（fMRI）方法，苯丙胺诱导的受体的时间尺度 内部化和回收将使用重复的苯丙胺管理建立。目标 多巴胺能阻断药物将与苯丙胺配对，以确定兴奋之间的平衡 D1和抑制性D2受体信号传导和运输会随着时间的推移而进行调节。重复的影响 然后，将苯丙胺与哌醋甲酯的苯丙胺进行比较，以评估不同水平的多巴胺潮流 以及这两种刺激性药物的作用机制。总体而言，这项研究将揭开大脑 - 通过对重复的刺激药物暴露而导致的宽分子和功能变化，通过成像 转化动物模型中活大脑中的多巴胺受体运输。结果将阐明角色 多巴胺D1和D2型受体适应，从而提供了对神经生物学的重要见解 重复刺激药物使用的机制与启动并最终预防药物有关 致敏和成瘾。